Exploring the involvement of Na pump inhibitor marinobufagenin in the interactions between age-associated vascular and neurodegenerative processes in cognitive impairment and Alzheimer's disease

探索Na泵抑制剂marinobufagenin在认知障碍和阿尔茨海默病中与年龄相关的血管和神经退行性过程之间的相互作用中的作用

• 批准号: 10913151
• 负责人: Olga V Fedorova
• 金额: $ 219.07万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10913151
• 关键词: Age; Aging; Alzheimer' s Disease; Analysis of Variance; Aorta; Blood Pressure; Blood Vessels; Brain; Breeding; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Clinical; Collagen; Consumption; Dahl Hypertensive Rats; Data Analyses; Dementia; Development; Diet; Disease; Echocardiography; Elastin; Elderly; Exhibits; Fibrosis; GDF15 gene; General Population; Genes; Hippocampus; Histocytochemistry; Hypertension; Impaired cognition; Impairment; Inflammation; Inflammatory; Left ventricular structure; Life; Linear Regressions; Measurement; Measures; Memory; Memory Loss; Microvascular Dysfunction; Modeling; Na(+)-K(+)-Exchanging ATPase; Nerve Degeneration; Pathology; Physiologic pulse; Process; Rattus; Regression Analysis; Risk Factors; Sodium Chloride; Sprague-Dawley Rats; TGFB1 gene; TP53 gene; Testing; Thick; Time; Vascular Dementia; Weight; arterial stiffness; design; epidemiology study; experimental study; hemodynamics; indexing; inhibitor; mRNA Expression; male; marinobufagenin; morris water maze; senescence; spatial memory

The following experiment was performed to test the study hypotheses: We used male SD and DSS rats, which were kept on a normal salt diet (0.5% NaCl; n=8/group) for entire experiment. The longitudinal repeated and non-repeated measurements were performed at 3-mo and 12-mo of age. The following groups were used: DSS-3, DSS-12, SD-3 and SD-12. Repeated measurements (systolic blood pressure, SBP; pulse wave velocity, PWV, an index of CAS; echocardiography), and non-repeated measurements (Morris water maze, MWM, to test spatial memory; aortic collagen, elastin (estimated by histochemistry), and left ventricle (LV) mRNA expression (qPCR) of the genes related to fibrosis, inflammation and senescence) were assessed at 3-mo and 12-mo of age. Data analyses was performed using linear mixed-effect 2-way ANOVA, t-test and linear regression (LR) modeling. We have demonstrated, that SBP, PWV, aortic weight, wall thickness and collagen/elastin ratio were higher in young DSS-3 vs. SD-3. These parameters were also higher in DSS-12 vs. DSS-3, whereas only PWV and aortic wall thickness were higher in SD-12 vs. SD-3. Relative left ventricle wall thickness (RWT) and LV expression of pro-fibrotic genes (collagen1a2, 1.5-fold; TGFbeta1, 1.8-fold); inflammatory gene (TNFalpha1, 1.7-fold), and senescence genes (GDF15, 3-fold; TP53, 1.9-fold) were higher in DSS-12 vs. DSS-3 rats, and in DSS-12 vs. SD-12 rats. DSS-12 spent more time to find a hidden platform in MWM vs. SD-12 (47 +/-3 sec vs. 27 +/- 4 sec; p<0.05). Impaired spatial hippocampal memory in DSS-12 was positively associated with PWV and LV mass by LR analysis. Based on the results of this study we have concluded, that: (1) EVA, indexed as higher BP, PWV and aortic remodeling were associated with early CV aging, manifested by activation of LV senescence, inflammatory and pro-fibrotic genes and by higher rates of age-associated changes in BP, RWT and LV mass in DSS vs. SD. (2) In DSS, EVA and early CV aging was associated with memory decline later in life. (3) The DSS rat model exhibits close similarity to clinical vascular dementia by sharing the presence of hypertension and CAS, which precede cognitive decline development.

为了检验研究假设，我们进行了以下实验： 我们使用雄性SD和DSS大鼠，它们被保持在正常的食盐饮食(0.5%的氯化钠；n=8/组)进行整个实验。在3个月龄和12个月龄分别进行纵向重复测量和非重复测量。使用DSS-3、DSS-12、SD-3和SD-12组。分别在3个月和12个月时进行重复测量(收缩压；脉搏波速度，CAS的一个指标；超声心动图)和非重复测量(Morris水迷宫，MWM，以测试空间记忆；主动脉胶原、弹性蛋白(组织化学估计)和左心室(LV)与纤维化、炎症和衰老相关基因的表达(QPCR))。数据分析采用线性混合效应双因素方差分析、t检验和线性回归(LR)建模。 我们已经证明，年轻的DSS-3比SD-3的SBP、PWV、主动脉重量、管壁厚度和胶原/弹性蛋白比率更高。DSS-12的这些参数也高于DSS-3，而SD-12的PWV和主动脉壁厚度仅高于SD-3。DSS-12组较DSS-3组和DSS-12组大鼠左室壁相对厚度(RWT)和促纤维化基因(胶原1a2，1.5倍；TGFbeta1，1.8倍)、炎症基因(TNFalpha1，1.7倍)和衰老基因(GDF15，3倍；TP53，1.9倍)的表达较高。与SD-12相比，DSS-12花了更多的时间在MWM和SD-12中寻找隐藏平台(47+/-3秒比27+/-4秒；p&lt；0.05)。LR分析显示，DSS-12患者的空间记忆障碍与PWV和LV质量呈正相关。 根据这项研究的结果，我们得出结论： (1)以BP、PWV和主动脉重构为指标的EVA与早期CV老化相关，表现为DSS组与SD组相比，LV衰老、炎症和促纤维化基因的激活以及BP、RWT和LV质量随年龄变化的比率更高。 (2)在DSS中，EVA和早期CV老化与晚年记忆减退有关。 (3)DSS大鼠模型表现出与临床血管性痴呆的相似性，表现为高血压和CAS的共同存在，先于认知功能减退的发展。